|Year : 2019 | Volume
| Issue : 3 | Page : 306-312
Pain control for laparoscopic hysterectomy with magnesium versus nalbuphine added to intraperitoneal bupivacaine: a randomized double-blinded study
Marwa A.K Elbeialy1, Marwa M Mowafi1, Mohamed A Elsenity2
1 Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||22-Jun-2018|
|Date of Acceptance||27-May-2019|
|Date of Web Publication||29-Aug-2019|
MD Marwa A.K Elbeialy
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Abbassia, Cairo 11591
Source of Support: None, Conflict of Interest: None
Background Pain control for laparoscopic hysterectomy carries some concerns. Intraperitoneal bupivacaine either alone or with additives has been studied with favorable results. However, adding nalbuphine has not been sufficiently examined. This study aimed to compare between the addition of magnesium sulfate (MgSO4) or nalbuphine to bupivacaine regarding efficacy and drawbacks.
Patients and methods A total of 80 female patients of American Society of Anesthesiologists I–II scheduled for laparoscopic hysterectomy in Ain Shams University hospitals were randomly distributed into two groups: group bupivacaine magnesium (BM) (n=40), in which patients received 30 ml of intraperitoneal bupivacaine 0.25% plus 30 mg/kg MgSO4, and group bupivacaine nalbuphine (BN) (n=40), in which patients received 30 ml of intraperitoneal bupivacaine 0.25% plus 5-mg nalbuphine at the end of operation. A standard general anesthesia technique was used in all patients. Visual analog scale, total intravenous diclofenac consumption, the time for first analgesia requirement, incidence of adverse effects, and patient satisfaction in the first 24 h postoperatively were recorded in both groups.
Results BN group experienced prolonged postoperative pain-free period. Total diclofenac consumption and pain scores were significantly less in BN group as compared with BM group. Regarding the adverse effects, there was insignificant difference between both groups for incidence of shoulder pain; however, BN group experienced more postoperative nausea and vomiting. Other adverse events were not reported. Patient satisfaction was significantly higher in BN group when compared with BM group.
Conclusion This study showed that addition of nalbuphine to bupivacaine for intraperitoneal instillation gave better postoperative pain control when compared with adding MgSO4 to bupivacaine.
Keywords: bupivacaine, hysterectomy, laparoscopy, magnesium sulfate, nalbuphine, postoperative pain
|How to cite this article:|
Elbeialy MA, Mowafi MM, Elsenity MA. Pain control for laparoscopic hysterectomy with magnesium versus nalbuphine added to intraperitoneal bupivacaine: a randomized double-blinded study. Res Opin Anesth Intensive Care 2019;6:306-12
|How to cite this URL:|
Elbeialy MA, Mowafi MM, Elsenity MA. Pain control for laparoscopic hysterectomy with magnesium versus nalbuphine added to intraperitoneal bupivacaine: a randomized double-blinded study. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Nov 21];6:306-12. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/306/265720
| Introduction|| |
Laparoscopic gynecological operations have gained popularity in the past years owing to their great benefits; they provide minimal incision size, resulting in a better cosmetic appearance, more patient satisfaction, and lower incidence of postsurgical wound infection . However, there are still concerns about the various ways to optimize postlaparoscopic pain with its different components, parietal, visceral, and shoulder pain, that may hinder full rapid recovery and prolong hospital stay ,.
Intraperitoneal instillation of local anesthetic agents with or without adjuncts has become an important method to control postlaparoscopic pain ,. Local anesthetics block the visceral afferent signals and modify visceral nociception, and also they provide antinociception by affecting nerve membrane-associated proteins and by inhibiting the release of prostaglandins that stimulate the nociceptors and boost the inflammatory process .
Magnesium sulfate (MgSO4) is N-methyl D-aspartate (NMDA) receptor antagonist  As these receptors regulate neuronal signaling and are involved in pain processing, MgSO4 decreases postoperative pain as well ,. It has been examined for intraperitoneal instillation in many studies with promising results ,,. Studies have also investigated intraperitoneal administration of various types of opioids ,, but nalbuphine has not been sufficiently studied. It is a known mixed agonist–antagonist opioid with agonist activity on kappa receptor, whereas antagonist action on mu receptors; because of such properties, it provides analgesia with lower incidence of adverse effects when compared with other pure opioid agonists like morphine ,.
The purpose of this study was to compare between the addition of MgSO4 or nalbuphine to intraperitoneal bupivacaine installation in laparoscopic hysterectomy for postoperative pain control and their relative adverse effects.
| Patients and methods|| |
This prospective double-blinded, randomized clinical trial had been carried at Ain Shams University Gynecology and Obstetrics Hospital on 80 female patients after obtaining approval of research ethical committee of Faculty of Medicine, Ain Shams University (code number: FMASU R49/2017). It was registered in the ClinicalTrials.gov (registration number: NCT03393572) database. Patients of classes I and II of American Society of Anesthesiologists (ASA) physical state classification aged 20–60 years and scheduled for laparoscopic hysterectomy were included in this study.
All patients were well informed about the study and signed a written informed consent. The exclusion criteria included ASA physical status more than II, obesity (BMI >30 kg/m2), history of chronic opioids intake, known hypomagnesemia or hypermagnesemia, chronic alcoholism, heart block, renal failure, patients with history of left ventricular failure, patients taking beta-blocking drugs, allergy to the study drugs, or if surgery changed to open hysterectomy. Using a computer-based randomization method and closed envelopes, patients were randomly assigned into two groups: group bupivacaine magnesium (BM) (n=40), in which patients received intraperitoneal 30 ml bupivacaine (sunnypivacaine, 20 mg vial contains bupivacaine HCL monohydrate 105.5 mg/Eq to 100 mg bupivacaine HCL; Sunny Pharmaceutical, Badr City, Cairo, Egypt) 0.25% plus 30 mg/kg MgSO4, and group bupivacaine nalbuphine (BN) (n=40), in which patients received intraperitoneal 30 ml bupivacaine 0.25% plus 5 mg nalbuphine (Nalufin, nalbuphine HCL 20 mg/ml; Amoun Pharmaceutical Co., S.A.E., El Obour City, Cairo, Egypt).
On the day before surgery, every patient underwent a thorough preoperative assessment. At the operating room, an 18-G intravenous catheter was inserted and crystalloid infusion was started, close monitoring of the patient was commenced via ECG, noninvasive blood pressure, oxygen saturation (SpO2), and capnography. Basal records of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and SpO2 were taken. Three minutes of preoxygenation with 100% oxygen was done, and then general anesthesia was induced with intravenous fentanyl 2 µg/kg and propofol 2.0–2.5 mg/kg and was followed by atracurium 0.5 mg/kg to facilitate endotracheal intubation. Then trachea was intubated with a cuffed endotracheal tube of appropriate size. Anesthesia was maintained with oxygen with 1% isoflurane. Atracurium was supplemented at 0.1 mg/kg guided by ulnar nerve stimulator monitoring. Minute ventilation was adjusted to keep normocapnia (end-tidal carbon dioxide between 34 and 38 mmHg).
Pneumoperitoneum was created by insufflations of carbon dioxide, and the operation table was tilted to about 15° Trendelenburg. Intraabdominal pressure was not allowed to exceed 15 mmHg. At the end of the procedure, those patients who were allocated to BM group recieved 30 ml of intraperitoneal bupivacaine 0.25% plus 30 mg/kg of MgSO4 intraperitonealy. Half amount of the solution was instilled on the inferior aspect of diaphragm (divided evenly on each side) and the remaining on the operative site via the umbilical port with patient in anti-Trendelenburg position after peritoneal wash and suctioning. For patients allocated to BN group, intraperitoneal instillation of 30 ml bupivacaine 0.25% plus 5 mg nalbuphine was in the same pattern. carbon dioxide was then evacuated from the peritoneal cavity, and the skin incisions were closed. The drugs were prepared by the study investigator, and the intraperitoneal instillation was done by the surgeon. Neither the surgeon nor the anesthetist following the patients intraoperatively was aware of the study drugs.
For reversal of muscle relaxation, 40 μg/kg neostigmine and 20 μg/kg atropine were given. Patients were transferred to the postanesthesia care unit after tracheal extubation when they are fully awake and responding to vocal commands. Visual analog scale (VAS) pain score was recorded immediately after extubation (considered as 0 time), at 30 min, and at 1, 2, 4, 6, 8, 12, 16, 20, and 24 h after surgery. All the study patients were instructed about the use of the VAS score before induction of anesthesia (VAS score 0 cm=no pain and VAS score 10 cm=worst possible pain). Total analgesic consumption in 24 h was recorded as well as time to rescue analgesia (considering the extubation is the 0 time). When VAS was more than or equal to 4, diclofenac 75 mg (declophen, diclofenac sodium 75 mg/3 ml; Pharco B International for Pharco Pharmaceuticals, Alexandria, Egypt) was given as a rescue analgesic as intravenous infusion (one ampoule diluted in 100 ml 0.9% normal saline given over 30 min). The incidence of postoperative shoulder pain was noted for the first 24 h.
Hemodynamic parameters such as HR, SBP, and diastolic blood pressure were recorded 5 min before induction (i.e. baseline parameters) and thereafter every 5 min for the first 20 min after administration of the study drugs. If SBP is 20% below the baseline or less than 90 mmHg, it was managed with intravenous boluses of 250-ml lactated Ringer’s solution or/and with ephedrine 3–6 mg, if needed. If bradycardia occurred (HR<60 beats/min), it was treated with atropine 0.5 mg bolus intravenous.
Adverse effects to the used drugs over 24 h postoperatively were noted. The severity of postoperative nausea and vomiting (PONV) during the first 24 h was recorded and categorized as ‘no PONV, mild PONV, moderate PONV, and severe PONV’ . Patients who were classified as moderate PONV or more received 4 mg of intravenous ondansetron. Incidence of pruritus and respiratory depression (defined as SpO2 less than 92% or respiratory rate less than 10 cycle/min) was also assessed.In addition, sedation was evaluated using Ramsay sedation scale (RSS) .
The patients were checked for analgesia satisfaction using five-point Likert scale in the ward by an anesthetist blind to the study, where 1=excellent, 2=very good, 3=good, 4=fair, and 5=poor ,.
The primary outcome was first time to ask for rescue analgesia postoperatively. The secondary outcomes were VAS score, total dose of analgesic consumption, and any adverse effects in 24-h postoperative period.
Sample size calculation
Using PASS program, setting alpha error at 5% and power at 80% and the results from a previous study showed that the mean time to rescue analgesia time was 5.53±4.33 h, whereas assumed for nalbuphine group to be 7.5±1 h. Based on this, the needed sample size is 40 cases per group (total 80).
The statistical analysis was performed using a standard SPSS software package, version 21 (SPSS Inc., Chicago, Illinois, USA). Normally distributed numerical data are presented as mean±SD, and differences between groups were compared using the independent Student’s t test. Nonnormally distributed numerical data are presented as median (interquartile range) and are compared using Mann–Whitney test, and categorical variables were analyzed using the χ2 test and are presented as number and percent. P value less than 0.05 is considered statistically significant.
| Results|| |
Regarding demographic data (age, weight, BMI, and ASA status) and length of operation, there was no statistically significant difference between both groups ([Table 1]).
VAS was significantly higher in the BM group in comparison with BN group at 1, 2, 4, and 12 h postoperatively. In contrast, it was significantly higher in BN group at 6 and 8 h postoperatively. There was no significant difference between both groups immediately postoperatively, at 30 min, and at 16, 20, and 24 h after that ([Table 2]).
Regarding total diclofenac consumption per 24 h, it was significantly higher in BM group when compared with BN group. Moreover, rescue analgesia time was significantly shorter in BM group when compared with BN group ([Table 3]).
|Table 3 Total analgesic consumption and rescue analgesia time in both groups|
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Regarding adverse effects, there was insignificant difference between both groups for incidence of shoulder pain; however, BN group experienced more PONV ([Table 4]). There were no reported cases regarding hemodynamic adverse events (hypotension or bradycardia), respiratory depression, or pruritus. RSS was not more than two at any time in both groups. Patient satisfaction was significantly higher in BN group when compared with BM group ([Table 5]).
| Discussion|| |
Despite the enormous advantages offered by laparoscopic surgeries, such as small incision size, less cosmetic disfigurement, and improvement of wound healing with subsequent short hospital stay , control of postoperative pain in such operations is raised as an issue . The pneumoperitoneum effect with the stretch of the abdominal cavity, inflammation of the peritoneum, phernic nerve irritation, and surgical incision are additive mechanisms for pain . This is augmented in laparoscopic hysterectomy by the relatively prolonged surgical time and extended head-down position .
Intraperitoneal instillation of local anesthetics had been introduced as a modality of analgesia as early as 1950 ; since that time, it had been examined extensively in literature to prove its utility . Their usage was found to decrease postoperative analgesic requirement in laparoscopic gyneocological procedures, referred to the study by Goldstein and colleagues that compared instillation of 20 ml of 0.5% bupivacaine or 0.75% ropivacaine versus placebo. This prompted them to recommend this mode of analgesia as routine in such operation . The assumption was to inhibit the visceral pain signals by blocking their conduction across the neuronal fibers; also the anti-inflammatory properties may contribute to the antinociception characteristics of local anesthetics .
The safety of the technique was shown in a study done by Narchi and colleagues. Mean plasma concentrations after instillation of 100–150 mg of plain bupivacaine intraperitoneally was found to be below the toxic levels of the drug (3 μg/ml) . In our study, we used only 75 mg of plain bupivacine, which is further below the previously mentioned dose, as we depended on additives to ensure prolonged effect.
It was found that combination of intraperitoneal bupivacaine with opioids is superior to the plain bupivacaine for the relief of postoperative pain in patients undergoing laparoscopic procedures with low incidence of significant adverse events. Several types of opioids had been investigated for intraperitoneal instillation either alone or as additives to local anesthetics as morphine ,, fentanyl , or tramadol . Nalbuphine is still not widely investigated for intraperitoneal route. Only two studies examined the drug either alone in comparison with lidocaine or placebo  or in combination with ropivicaine versus ropivicaine alone for intraperitoneal instillation . They did not compare its combination with bupivacaine or versus other additives such as MgSO4. Nalbuphineisa highly lipid-soluble opioid  that lacks the agonist effect on µ-receptors, so it provides more cardiovascular stability with less nausea and vomiting, minimal sedation, and less respiratory depression .
Intraperitoneal MgSO4 either alone  or in combination to local anesthetics  was also found to have beneficial effects for laparoscopic procedures. Several studies demonstrated its analgesic effects in animals and humans. This may be attributed to its property as natural antagonist to calcium influx into cells. Moreover, it can hinder the central sensitization to pain by blocking NMDA receptors .
The most intense pain postlaporscopically was found to be of visceral origin, and its peak effect was experienced during the first hour postoperatively, which increased by respiration, coughing, and mobilization .
In the current study, the pain score analysis revealed no significant difference between BM and BN groups immediately postoperatively and at 30 min, but it appears to be higher in the BM group at 1, 2, and 4 h. However, the reverse occurred at 6 and 8 h. as pain scores became higher in the BN group; this may be owing to the effect of rescue analgesic in the BM group and the wearing effect of the drug in the BN group. After that there was no significant difference between both groups till the end of the 24 h. Moreover, patients in the BM group experienced less pain-free period when compared with patients in BN group (3.65±1.49 vs. 5.63±1.31 h, respectively; P<0.001) with more total diclofenac requirement (136.88±28.86 vs. 110.63±37.93 mg, respectively; P<0.001) during the first 24 h postoperatively.
In a study done by Morsy and Mohamad Abdalla, it was found that VAS was lower in patients who received intraperitoneal instillation of 200-mg lidocaine or 10-mg nalbuphine in 50-ml saline compared with placebo group during the first 8 h; they also reported that there was no difference between groups detected later for the first 24 h .
In a study conducted by Singh and colleagues, the pain intensity was lower in patients who received 20 ml of intraperitoneal 0.2% ropivacaine with 2-mg nalbuphine compared with those who received intraperitoneal saline during the first 8 h after recovery. Moreover, the total dose of rescue analgesics used was markedly reduced in patients with intraperitoneal ropivacaine and nalbuphine group .
Abdel–Raouf and Amer  studied the postoperative analgesic effects of intraperitoneal 30 mg/kg MgSO4 and 1 mg/kg of ketamine as NMDA receptor antagonist, along with intraperitoneal 0.25% bupivacaine in patients undergoing laparoscopic cholecystectomy. They showed that time to first analgesic requirement in NMDA receptor antagonist was around 130 min after surgery compared with control and bupivacaine group (15.30 and 35.30 min, respectively). Moreover, less analgesia was needed in the magnesium bupivicaine group. This came in agreement with the results of our study; however, we experienced a relative prolonged time to rescue analgesia in magnesium group.
Moreover, our results came with Maharjan and Shrestha  and Ali et al. . Maharjan and Shrestha compared intraperitoneal instillation of bupivacaine, alone and in addition to MgSO4. Intraperitoneal bupivacaine plus 50 mg/kg MgSO4 at the end of surgery had better pain relief for a period of 2–5 h compared with patients who were given intraperitoneal bupivacaine alone.
In the study done by Ali et al. , the mean pain scores (VAS) were significantly lower in patients who received intraperitoneal 20 mg/kg MgSO4 immediately after establishment of pneumoperitonium when compared with the control group in first 6 h postoperatively. Moreover, total analgesic consumption was higher in the control group.
There was no significance difference between both groups regarding shoulder pain. Clinically, intraperitoneal NMDA receptor antagonist MgSO4 with bupivacaine reduced postoperative shoulder pain  Regarding intraperitoneal nalbuphine, Singh et al.  demonstrated that it was associated with lower incidence of shoulder pain in combination with ropivacaine compared with the control saline group.
Regarding PONV, overall there was low incidence in both groups, with just a few cases of mild PONV that did not need administration of antiemetic; however, they were more with BN group (20%) when compared with the BM group (5%). Even though there are no recent data on the usage of the NMDA antagonists as antiemetics, there was evolving research on such spectrum since 1998, and it was found that magnesium may block NMDA receptors in the emetic pathways .
These results came with agreement with the results of a study done by Morsy and Mohamad Abdalla  who found that the incidence of PONV was more in patients given intraperitoneal nalbuphine or saline when compared with patients given intraperitoneal lidocaine.
There were no reported cases in the current study regarding respiratory depression in both groups in the first 24 h. Moreover, RSS was not more than two at any time of assessment.
This was in contrary to the study by Ali et al.  who reported excessive sedation in patients who received intraperitoneal MgSO4 when compared with control group.
Morsy and Mohamad Abdalla  found that patients in nalbuphine group had high incidence of puritus when compared with patients in the lidocaine group, and it was statistically significant. There was no difference between both groups in our study regarding the incidence of pruritus. Generally, patients in the BN group showed more satisfaction with the modality of analgesia used when compared with BM group. This may be owing to the prolonged pain-free period experienced by them with relatively low incidence of adverse events.
However, our study was associated with some limitations as it lasted only for the first 24 h, we did not measure the serum concentrations of drugs after administration, and we did not analyze the type of pain experienced by patients.
| Conclusion|| |
The current study showed that addition of nalbuphine to bupivacaine for intraperitoneal instillation in laparoscopic hysterectomy operation gave better postoperative pain control when compared with adding magnesium to bupivacaine.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]